18. antibiotic use in the ic ul
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Antibiotics in the ICU Antibiotics in the ICU
Ram E. Rajagopalan,MBBS, AB (Int Med) AB (Crit Care)
Department of Critical Care Medicine
SUNDARAM MEDICAL FOUNDATIONChennai
Choice, Resistance, Pharmacokinetics & Pharmacodynamics
Nosocomial InfectionBetween 30-40% ICU patients have or develop infectionAbout ½ of these are nosocomial
Prevalence is very variable between different kinds of units
Bacteriologicallyconfirmed
(true positive)
“Anticipated” infection
Clinicallysuspectedinfection
Antibiotic use in the ICU
Empirical Rx
Definitive Rx
Prophylactic Rx
Indications for antibiotics ~ 60% of patients in a general ICU receive antibiotics
Bergmans et alJAC 1997; 39: 527-35
Inci
sion
Tim
e
Time of Prophylactic dose
Rat
e of
Wou
nd In
fect
ion
Antibiotic Prophylaxis
Only for “clean-contaminated” & some “clean” wounds Appropriate cover; No value for additional doses
One dose..
..one hour before....incision
SURGICAL WOUND
Antibiotic Use & Resistance
Habarth et al.Circulation 2000; 101: 2916-21
….but prolonged ABP was an independent risk factor for bacterial resistance (AOR 1.6; 95%CI: 1.1-2.6)
2641 CABG patients; 4-yr. observ. cohortEither < or > 48 hr antibiotic prophylaxis
Systemic Antibiotic Use
0
5
10
15
20
25
30
35
0 5 10 15 20
Days of ventilation
% w
ith V
AP
No Abx
Prior Abx
Resistant Ps. aeroginosa; Acinetobacter
19%
65%
ARRD 1989; 139:877–84.
Ventilator AssociatedPneumonia
Policy on Prophylaxis
Limit antibiotic prophylaxis to surgicalwounds; ideally one pre-op. dose
Avoid forPreventing pneumonia in intubated ptsPreventing bacteremia from CV linesPreventing UTI from a Foley’s catheter
#1Prevention Cure
Empirical AntibioticsSuspected InfectionEmpirical Treatment
Infection:Subsequentlyconfirmed bybacteriology
Infection:not confirmable(false negative)
No infection(SIRS)
? Over treatment
25-40%60-75%
ICEM Yearbook 2003; 218-228.
Assumptions for use of Empirical AntibioticsNosocomial infection increases (attributable) mortality
Antibiotic treatment reduces mortality
Early administration of correct antibiotic improves survival
Adverse effects are less than the benefits of treatment
Is death attributable to NI?
NI
Treat Don’t Treat
Is there a difference?
Yes No
NI kills Patient dies ofcritical illness
RIPRIP
Definition:Mortality caused by an infection (in excess of mortality in a similarly ill patient without infection).
Does Rx improve survival?
35 Clinical Trials identified
None placebo controlledOnly 2 double-blind
No “Gold Standard” antibioticMainly comparing antibiotic regimensMainly “equivalence” trials
NO DIFFERENCE BETWEEN AGENTS
Where are theEmperors clothes?
ICEM Yearbook 2003; 219-28.
Is death attributable to NI?Cohort of ICU Patients
NI No NI
Rx No (appropriate) Rx
Severity of illness is a confounder;May be adjusted by case-control studiesor Multivariate (regression) analysis
About 25% attributable mortalityRIPRIP
Definition:Difference in death rates between infected & uninfected patients after adjusting for confounders
Attributable Mortality
Nosocomial AttributableInfection mortality
All Nosocomial Infection 20% (2.8-44)Blood-stream 25% (4.4-47.3)Vent. Assoc. Pneumonia 25% (7.8-42)Urinary Tract NoneChest 2001; 120:2059–93
RIPRIP
Effect of Appropriate Choice
Luna et al; Chest 1997; 111: 676-85.
0
10
20
30
40
50
60
70
80
90
100
No Rx Correct Rx Incorrect
Hos
pita
l Mor
talit
y (%
)
Effect of Appropriate Timing
0
10
20
30
40
50
60
70
80
90
100
Early Late
None Correct Incorrect
Hos
pita
l Mor
talit
y (%
)
Luna et al; Chest 1997; 111: 676-85.
Timing and Mortality
Iregui et al Chest 2002; 122:262–8
No Delay12.5 + 4.2 h
Delay28.6 + 5.8 h
Tim
e fr
om D
x of
VA
P (h
)
20
40
n=107
Delay increased hospital mortality 2.5x& VAP attributable mortality 3.5x
RIPRIP
Design Flaws
VAPRx
Culture + Culture -
Appropriate Inappropriate ?
Colonization by resistant bugs& subsequent adverse outcome
25% 75%
Making the Choice
Appropriately timed, appropriately chosen antibiotic can save lives…….so…. ….which antibiotic(s)?
Focused Rx with narrow spectrum (or)
Gorillamycin + Supersporin +
King-Kongopenem?
CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen
Pseudomonas (46)
30%
(13/44)
24%
(11/46)
23%
(10/43)
36%
(16/44)
46%
(21/46)
60%
(26/44)
64%
(7/11)
Klebsiella ESBL (38)
0%
(0/38)
5%
(2/38)
26%
(10/38)
35%
(13/37)
32%
(12/38)
37%
(14/38)
80%
(8/10)
E Coli ESBL (36)
0% 3%
(1/36)
- 58%
(21/36)
53%
(19/36)
67%
(24/26)
82%
(9/11)
Acinetobacter (15)
8%
(1/12)
31%
(4/13)
73%
(8/11)
75%
(9/12)
55%
(6/11)
36%
(4/11)
100%
(3/3)
Proteus (18)
72%
(11/15)
11%
(2/18)
11%
(2/18)
67%
(12/18)
100%
(15/15)
87%
(13/15)
100%
(2/2)
Non-ESBL (K+Ec) (15)
100%
(15/15)
93%
(14/15)
- 100%
(15/15)
100%
(10/10)
100%
(10/10)
100%
(2/2)
Antibiogram ™: SMF ICU Nosocomial Pathogens,
Antibiotics & Resistance
Widespread use of antibiotics leads to the selection of antibiotic resistant strains
Archibald et al; ICAREClin Inf Dis 1997; 24: 211-15
Evidence:Resistant organisms are more common amongst inpatients
ICUs (with highest use) have highest rates of resistance 0
5101520253035404550
% R
esis
tant
Org
anis
ms
MRSAMRSE
Pseud C
TZVRE
Inpatient
Outpatient
p <0.01 for all comparisons
“De-escalation”
Chest 2002; 122:2183–2196.
De-escalate Rx
Lab confirmed
Initial Rxwide-spectrum
Suspectinfection
Culture-basedde-escalation can reduce resistance
Policy on Empirical Rx
a. Empirical Rx can be justified in ICUb. Abx. choice based on local patterns c. Initial Rx should be wide-spectrum d. De-escalate based on culture result
As choice is based on local susceptibility& de-escalation needs culture resultsCULTURE prior to antibiotics is MANDATED!
#2
Policy for Definitive Therapy
Critically ill patients have microbiological colonisation of normally sterile sites
Treat true infection
Aviod antibiotics for colonised patients
!#3
Microbe Culture in VAP
Prob
abili
ty
1 2 3 4 5 6
VAP
Log CFUs
No VAP
CCM 2003; 31: 2544 – 51.
Routine culture of sputumDoes not differentiate infection vs. colonization
Quantitative or semi-quantitative culturesare needed
Responsible Use
1. Identify the site of infection
2. Know your bacteria
3. Maximise efficacy / minimise toxicity Appropriate dose ; PK-PD understood Drug level monitoring Duration
#4
Identify Site
SMF ICU 2001
05
1015202530354045
Pneumonia Bacteremia Urinary Tract
Pseudomonas Klebsiella E. Coli
Proteus Staph aureus Enterococcus
CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen
Pseudomonas (46)
30%
(13/44)
24%
(11/46)
23%
(10/43)
36%
(16/44)
46%
(21/46)
60%
(26/44)
64%
(7/11)
Klebsiella ESBL (38)
0%
(0/38)
5%
(2/38)
26%
(10/38)
35%
(13/37)
32%
(12/38)
37%
(14/38)
80%
(8/10)
E Coli ESBL (36)
0% 3%
(1/36)
- 58%
(21/36)
53%
(19/36)
67%
(24/26)
82%
(9/11)
Acinetobacter (15)
8%
(1/12)
31%
(4/13)
73%
(8/11)
75%
(9/12)
55%
(6/11)
36%
(4/11)
100%
(3/3)
Proteus (18)
72%
(11/15)
11%
(2/18)
11%
(2/18)
67%
(12/18)
100%
(15/15)
87%
(13/15)
100%
(2/2)
Non-ESBL (K+Ec) (15)
100%
(15/15)
93%
(14/15)
- 100%
(15/15)
100%
(10/10)
100%
(10/10)
100%
(2/2)
Antibiogram ™: SMF ICU Nosocomial Pathogens
ExtendedSpectrumBeta Lactamase(Klebsiella)
2002
7x
The ESBL “Plague” Plasmid-mediated resistanceVery high frequency in Indian Hospitals
MYSTIC study; Mathai et alDiag Mic Inf Dis 2002; 44: 367-77.
~70% of E. coli / Klebsiella all over India >50% in Anna Nagar ‘community’ >80% in SMF ICU
Cross-species transmission amongst enterobactereaciaeWide resistance to all beta-lactams including cephalosporins !
ESBL in the Developing World
Site Location %ESBLKlebsiella E. coli
AIIMS, New Delhi1 Tertiary Hospital 80% -Mathai 10 Tertiary Hosps. - >60%KGMC, Lucknow2 Neonatal ICU 86% 64%SMF, Chennai Nosocomial: ICU 84% 82%SMF, Chennai Comm. Acquired: ICU 53% 44%
China, Shanghai3 University Hospital 51% 24%Latin America4 SENTRY, Pneumonia 44% 29%
1: Ind J Med Res 2002;115:153-7 2: J Med Microb 2003; 52: 421-5 3: Zhou Yi Xue Za Zhi 2002;82:1476-9 4: Diag Mic Inf Dis 2002; 44: 301-11
What provokes ESBL Resistant Organisms?
Chest 2001; 119: 397S - 404SChest 2001; 119: 391S - 396SAJRCCM 2000; 162:1610-16J Hosp Infect 2003 ; 53: 39-45JAMA 1999; 281: 517-23
Are there identifiable risk groups?Prior 3rd Gen Ceph. Poor Functional Status
High APACHE score>5 days in ICUDecubitus ulcersInstrumentation
Community wide use of ciprofloxacin or co-trimoxazole!
Does ‘ESBL’ kill?Case control study from Israel (198 patients)
Multivariate analysis;
ESBL remains independently associated withMortality OR 3.6 (1.4 - 9.5) p <0.008Delayed Rx OR 25.1 (10.5 - 60.2) p <0.001LOS OR 1.56 p <0.001Cost OR 1.57 p <0.003
RIPRIP
Antimicrob Agents Chemo 2006; 50: 1257-62
Treating ‘ESBL’:
Chest 2001; 119: 391S - 396S.Diag Mic Inf Dis 2002; 44: 367-77.
Carbepenems are drugs of choice
Avoidance of all 3rd gen. CephalosporinsTraditional choices for ‘serious’ gram negative infectionsIn-vitro sensitivity may be spurious
4th Generation Ceph. may be effective
B-lactam / lactamase inhibitors; recommended but have high rates of resistance
Aminoglycoside, quinolone resistance common
Minimizing ESBL ResistanceRestriction of Ceftazidime alone is not effective
Hospital- wide restriction of 3rd generation cephalosporins
Use of B-lactam/ lactamase inhibitor for empirical therapy
Good infection control measuresJAMA 1998; 280: 1233-7
MDR AcinetobacterIncreasing prevalence and outbreaks
Gram negative “cocco-bacillus”
Ventilator Associated PneumoniaBacteremiaSecondary meningitis / ventriculitisSkin infectionsEndocarditisCAPD-peritonitis
TEM1 / CARB mutationESBLOxa- beta lactamaseCarbepenemaseA/G, quinolone resist
Environmental Sources of Acinetobacter
Bed rails Bedside tables Ventilators Infusion pumps Mattresses Pillows Patient monitors
X-ray view boxes Curtain rails Curtains Equipment carts Sinks Ventilator circuits Floor mops
Infect Control Hosp Epidemiol.
2003;24: 284-95
Risk Factors for Acinetobacter
Ventilator Assoc. Pneumonia
Age Chronic lung Dx Immunosupress. Prior antibiotic Rx Invasive Device Prolonged ICU stay
Bloodstream
Infection
Respiratory failure Prior Antibiotics Invasive device________________________________________________
72% of BSI has a lung
sourceCID; 2001; 33: 939-46
Impact of Acinetobacter in the ICUOutcome Group Any infection Pneumonia
MortalityCases 58% 70%
Controls 15% 17%
Attributable mortality
43% 53%
Risk ratio for death
4.0
(CI951.9-8.3)
4.0
(CI951.6-10.2)
Length of stay (median)
Cases 23 days 23 days
Controls 10 days 10 days
Excess LOS 13 days 13 days
Crit Care Med 1999;27:1794-1799. 48 patients 1:1 case control study
Impact of A. baumanii Resistance
Outcome Group All Imipenem (R)
MortalityCases 40% 44%
Controls 28% 24%
Attributable mortality
12%P=NS
20%P=NS
Length of ICU stay (median)
Cases 35 days
Controls 37 days
Excess ICU LOS-2 days
P=NS
Crit Care Med 2003;10:2478-2482. Historical cohort study; 60 patients with A. baumanii VAP matched 1:1 to Controls
Acinetobacter: Rx Options
Carbepenem (if no resistance)Colistin / Polymixins (aerosol?)Sulbactam (ampi-sulb; cefperazone-sulb)
66
33
21
86
37
47 47
0
20
40
60
80
100
Amp/sulb Pip Cefotaxime Imipenem Cipro Gent TMP/SMX
MDR, A. baumaniIs resistant to chlorhexidine
J Hosp Infect 2002;51:106-113.
TSN Database
QuinolneResistantPseudomonas Aeroginosa
0
5
10
15
20
25
30
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Per
cen
t R
esis
tan
ce
2002
3x
Carbepenem Resistant P. aeruginosaIncreasing prevalenceAmp C mechanism; beta lactams induce
Carbepenem resistance:Mutational porin channel lossAcquired metalo-beta-lactamases (integrin)
Treat: Colistin, Aminoglycoside, Quinolone, 4th G Cephalosporin
Prevent: ? multi-agent Rx of all ICU P. aeruginosa
MethicillinResistantStaphylococcusAureus
2002
How About MRSA?
Quite common; VAP, bacteremia
Risk factors: Age, severity of illness,prior antibiotic use, instrumentation*
Attributable mortality (>MSSA) debatable
Prefer Vancomycin for Rx even in VAP or severe CAP; equivalent efficacy@ to linezolid
*Ann Intern Med. 2002; 136: 834-44@J Anti Chemo 2003; 51(S2): ii27-35
Pharmacokinetics: VdPharmacokinetics is altered and variable in critically ill
Volume of distribution (Vd) can change significantly in any individual with changing fluid balance
Vd is vastly different between patients
Implication: Regardless of organ dysfunction most drugs need to be “loaded” at normal or higher doses.
Drug level measurement would be ideal
Surgery 1998; 124: 73-8J. Chemother 1995; 7: 45-9Intens Care Med 2001; 27: 363-70Ant Ag & Chemo 2002; 46:1557-60Intens Care Med 2004; 30: 2145–56
Clearance: Renal FunctionIncreased Vd : Due to fluid retention Vd and Renal failure = clearance
Calculated Creatinine clearance / GFR** MDRD or Cockraft-Gault method are poor
: in acutely ill with changing renal function: severe muscle wastingMeasured values ideal
CRRT similar to GFR ~35 ml/min* CVVHD clears < 50 Da molecular weightCVVF clears larger molecules (>1100 Da)
*Intens Care Med 2004; 30: 2145–56**N E J Med 2006; 354: 2473-83
Clearance: Liver FunctionLiver function does not affect most antibiotic clearances significantly
Hypoalbuminemia may increasefree antibiotic levels, but again the effect is modest and does not affect treatment
Chloramphenicol, clarithro, erythro, clinda,
metronidazole, nafcillin, tetracycline… may need some dose adjustmentIntens Care Med 2004; 30: 2145–56
Pharmacodynamics
MBCMIC
Bac
teria
l Cou
nt a
t site
Ant
ibio
tic C
onc.
Post Ab Effect
Pharmacodynamics:Defines the Interaction of the drugs and the microbes
Inf Dis Clin NA 2004; 18: 451-65
Concentration Dependent
MBCMIC
Bac
teria
l Cou
nt a
t site
Ant
ibio
tic C
onc.
Peak
AUC
Indicators of efficacy:Peak / MIC ratioAUC / MIC ratio
Inf Dis Clin NA 2004; 18: 451-65
Agents:QuinolonesAmphotercinAminoglycosidesMetronidazole
Time Dependent
MBCMIC
Bac
teria
l Cou
nt a
t site
Ant
ibio
tic C
onc. Time > MIC
Inf Dis Clin NA 2004; 18: 451-65
Indicators of efficacy:Time above MICPreferably > 50%
Agents:PenicillinsCephalosporinsCarbepenemsGlycopeptidesMacrolidesLinezolid
Value of PK / PDBetter Drug Dosing: Once-a-day aminoglycoside therapy
Better interpretation of antibiotic levels-improved responses
Population studies allows better identification of MIC breakpoints
Better dosing to minimize emergence of resistance
Duration of TreatmentWhat is the optimal duration of antibiotic
administration?
Guaranteecure
Minimize costMinimize resistance
Should resistant strains be subjected to longer treatment courses?
JAMA 2003; 290: 258-98
0 1 2 3 months
0 1 2 3 months
0 1 2 3 months
Restrict
Rotate
Heterogeneous use
Gorillamycin Supersporin Kingkongopenem
Rotation
Strategies to Reduce Resistance
Abx 2 Abx 3 Abx 1
Res
ista
nce
Abx 1
Presumed that the decline in resistance with antibiotic cessation would be at least as fast as the emergence of resistance.
Time
None of the evidence is “clean” Mainly observational cohorts Some studies are of a single scheduled
change (not rotation) Associated confounders:
Antibiotic restriction policies Infection prevention strategies
Often evaulate nosocomial infection alone not colonisation rates
RCTs are needed
Rotation: The Evidence?
Gerding et alAAC 1991; 35: 1284-90
Koleff et alAJRCCM 1997; 156: 1040-8
Gruson et alAJRCCM 2000; 162: 837-43
Raymond et alCCM 2001; 29: 1101-8
Toltzis et alPaediatrics 2002; 110: 707-11
Strategies to Reduce ResistanceRestriction, Rotation, ?Rubbish…
Res
ista
nce
Abx 2 Abx 3 Abx 1Abx 1
Resistance emerges fast (with antibiotic use) but…… declines slowly (with cessation of use)*
Antibiotic cycling is inferior to “heterogeneous” use**
*Austin et alProc Nat Ac Sci 1999; 96:1152-56
**Bonhoeffer et alProc Nat Ac Sci 1997; 94: 12106-11
The Power of BacteriaAge:Bacteria 3,500,000,000 years (2000x)Eukaryotes 1,800,000,000 years (1000x)Multicellulars 580,000,000 years (300x)Australopithecus 4,000,000 years (2x)Homo erectus <2,000,000 years (1)Antibiotic use 60 years (0.00003x)
Numbers:“ The number of E.coli in the gut of each human being far exceed the number of people that now live or have ever inhabited the earth” !!!
They are ubiquitous and indestructibleGould SJ. Life’s Grandeur; Vintage (Pub), 1997.